Treating Cancer by Targeting Telomeres and Telomerase.
Treating Cancer by Targeting Telomeres and Telomerase.
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DOI：
10.3390/antiox6010015
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发表时间：
2017-02-19
期刊：
影响因子：
--
通讯作者：
Puri N
中科院分区：
文献类型：
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作者：
Ivancich M;Schrank Z;Wojdyla L;Leviskas B;Kuckovic A;Sanjali A;Puri N
端粒酶在85%以上的癌细胞中表达。具有转移潜能的肿瘤细胞可能具有高端粒酶活性，允许细胞逃避由于缩短的端粒而导致的细胞增殖抑制。人端粒酶主要由两个主要组分组成：hTERT，催化亚基，和hTR，RNA模板，其序列与端粒5′-dTTAGGG-3′重复序列互补。在人类中，端粒酶活性通常仅限于更新组织，例如生殖细胞和干细胞，并且在正常细胞中通常不存在。虽然hTR在大多数组织类型中组成型表达，但hTERT表达水平足够低，以至于不能维持端粒长度，这在正常细胞上设定了增殖寿命。然而，在大多数癌症中，端粒酶保持稳定的端粒长度，从而赋予细胞永生。hTERTmRNA的水平与端粒酶活性直接相关，从而使其成为比hTR更合适的治疗靶点。最近的数据表明，端粒G-四链体的稳定化可能通过阻断hTR结合来间接抑制端粒酶作用。端粒DNA具有自发形成分子内G-四链体的倾向，所述分子内G-四链体是通过平面排列中的鸟嘌呤残基的堆叠而稳定的四链DNA二级结构。端粒G-四链体的功能作用尚未完全了解，但最近的证据表明，它们可以在DNA合成过程中阻止复制叉，并通过阻止端粒酶和相关蛋白与端粒结合来抑制端粒复制。用G-四链体稳定剂长期治疗诱导端粒的富含G的3'端的长度逐渐减少，而不减少总端粒长度，这表明端粒酶活性被抑制。然而，直接或间接地抑制端粒酶在癌症患者中仅显示出适度的成功。另一种有希望的靶向端粒的方法是使用与3'端粒突出端序列（T-oligo）同源的富含鸟嘌呤的寡核苷酸（GRO）。T-寡核苷酸，特别是称为T11的特异性11碱基寡核苷酸（5 '-dGTTAGGGTTAG-3'），已显示在许多癌细胞类型中诱导DNA损伤反应（DDR），如衰老、凋亡和细胞周期停滞，而在正常非转化细胞中具有最小或无细胞生长抑制作用。因此，T-oligos和其他GRO正在被研究作为前瞻性抗癌治疗剂。有趣的是，在癌细胞中由T-oligos诱导的DDR与正常细胞中进行性端粒降解后观察到的效果相似。端粒的丢失是一种重要的肿瘤抑制机制，在转化的恶性细胞中通常不存在，因此，T-oligos作为对抗癌症的新策略引起了人们的极大兴趣。然而，对其作用机制知之甚少。在这篇综述中，我们讨论了目前的理解如何T-寡核苷酸发挥其抗肿瘤细胞增殖的作用和抑制端粒酶的作用。我们还讨论了目前对端粒酶在癌症中的理解以及与端粒和端粒酶相关的各种治疗靶点。
Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effects in cancer cells and their role in inhibition of telomerase. We also discuss the current understanding of telomerase in cancer and various therapeutic targets related to the telomeres and telomerase.